title: CXCL1 and its receptor, CXCR2, mediate murine sickle cell vaso-occlusion during hemolytic transfusion reactions.
abstract: Hemolytic transfusion reactions (HTRs) can produce serious and potentially life-threatening complications in sickle cell disease (SCD) patients; however, the mechanisms underlying these complications remain undetermined. We established a model of alloimmune, IgG-mediated HTRs in a well-characterized humanized murine model of SCD. HTRs induced acute vaso-occlusive crisis (VOC), resulting in shortened survival of SCD mice. Acute VOC was associated with elevated circulating inflammatory chemokine levels, including striking elevation of the levels of the neutrophil chemoattractant CXCL1. Recombinant CXCL1 administration was sufficient to induce acute VOC in SCD mice, characterized by leukocyte recruitment in venules, capture of circulating red blood cells, reduction of venular flow, and shortened survival. In contrast, blockade of the CXCL1 receptor, CXCR2, prevented HTR-elicited acute VOC and prolonged survival in SCD mice. These results indicate that CXCL1 is a key inflammatory mediator of acute VOC in SCD mice. Targeted inhibition of CXCL1 and/or CXCR2 may therefore represent a new therapeutic approach for acute VOC in SCD patients.
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Jang
authors.forename: Eldad A
authors.initials: EA
authors.lastname: Hod
authors.forename: Steven L
authors.initials: SL
authors.lastname: Spitalnik
authors.forename: Paul S
authors.initials: PS
authors.lastname: Frenette
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D000818:Animals; D054360:Chemokine CXCL1 / Q000008:administration & dosage / Q000276:immunology*; D004195:Disease Models, Animal; D006461:Hemolysis / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010671:Phenylurea Compounds / Q000494:pharmacology; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000276:immunology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology; D065227:Transfusion Reaction; D014652:Vascular Diseases / Q000209:etiology* / Q000276:immunology; D014699:Venules / Q000276:immunology / Q000473:pathology / Q000503:physiopathology
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D010671:Phenylurea Compounds; D023063:Receptors, Interleukin-8B; D011994:Recombinant Proteins; C112019:SB 225002